Cancer mortality results in part from the development of variant tumor cells with a highly invasive and metastatic phenotype. The molecular events that contribute to the invasive/metastatic phenotype are poorly understood. Recent studies indicate that adhesion mediated signaling events involving a protein complex consisting of focal adhesion kinase (F AK), the Src protooncogene, and the Crk-associated substrate (CAS) function to regulate cell growth and migration. Other studies have linked these molecules to tumor invasion and metastasis. The broad long-term objective of the proposed studies is to determine if aberrant FAK-Src-CAS signaling contributes to the acquisition of the invasive/metastatic phenotype of human cancers. Toward this objective, the following three Specific Aims are planned: 1) Determine CAS protein-interaction motifs required for adhesion-regulated signaling, cell spreading, and migration; 2) Determine the role of GAS in Src-mediated cell transformation, invasion, and metastasis; and 3) Determine if enhanced signaling from the FA K-Src nexus can elevate the tumorigenic and metastatic potential of human colon carcinoma cell Iines. This work will help define the biological changes that underlie cancer spread and may lead to new preventive or treatment interventions.